The theme of this human research project of the Center involves mechanistic studies of opioid withdrawal across several levels of analysis. Four studies are proposed over a five-year period. Study 1 (year 1) will complete our ongoing study of the duration of action of buprenorphine. This study is determining whether mu-opioid receptor (mu OR) binding potential, measured using the mu-selective radiotracer [11-C]-carfentanil and positron emission tomography (PET), increases with time (4, 28, 52 and 76 hr; using dose omission) since the last daily buprenorphine dose (16 mg). Study 2 (years 2-4) will determine whether mu OR binding potential increases with time (4, 28 and 52 hr) since the last methadone dose (100mg). mu OR binding potential in Studies 1 and 2 will be correlated with plasma levels (pharmacokinetics) and saliva cortisol levels; spontaneous opioid withdrawal symptoms, delayed discounting of heroin; and the ability of methadone to attenuate effects of hydromorphone (HYD; cumulative doses of 0, 6, 12 and 24 mg IM). Study 3 (years 2-5) will first determine prior to methadone induction whether delayed heroin delivery (hypothetical choices on a time scale ranging from hours to weeks) is discounted during opioid withdrawal based on participants' naturalistic experience with heroin use, relative to the absence of withdrawal. Subsequently, during methadone maintenance that suppresses withdrawal and drug use, we will determine whether delayed heroin delivery is discounted during precipitated withdrawal (naloxone) relative to the absence of withdrawal (saline) in the same individuals. These parallel within-subject assessments are designed to establish whether rates of heroin discounting generalize across contexts. Discounting functions in Study 3 will also be compared to those in Study 2. Study 4 (years 2-5) will determine in methadone-maintained participants whether naloxone-precipitated withdrawal produces greater delayed discounting of actual HYD injections. Fifteen min. after saline or naloxone pretreatment, participants will choose between a smaller dose of HYD (12 mg IM) immediately or a larger dose of HYD (24 mg IM) given at increasing times (15, 30, 60, and 120 min) after pretreatment. We predict that withdrawal will enhance 'impulsive' HYD (12 mg) choice. Overall, this research component in the Center will advance theoretical knowledge of the neurobehavioral mechanisms underlying opioid reinforcement and physical dependence--which may provide insights useful in promoting drug abstinence and preventing relapse in treatment settings.